Subversion of NK Cell and TNF-alpha Immune Surveillance Drives Tumor Recurrence.

Understanding how incompletely cleared primary tumors transition from minimal residual disease (MRD) into treatment resistant, immune-invisible recurrences has major clinical significance. We show here that this transition is mediated through the subversion of two key elements of innate immunosurveillance. In the first, the role of TNF alpha changes from an antitumor effector against primary tumors into a growth promoter for MRD. Second, whereas primary tumors induced a natural killer (NK)-mediated cytokine response characterized by low IL6 and elevated IFN gamma, PD-L1(hi) MRD cells promoted the secretion of IL6 but minimal IFN gamma, inhibiting both NK-cell and T-cell surveillance. Tumor recurrence was promoted by trauma or infection like stimuli inducing VEGF and TNFa, which stimulated the growth of MRD tumors. Finally, therapies that blocked PD-1, TNF gamma, or NK cells delayed or prevented recurrence. These data show how innate immunosurveillance mechanisms, which control infection and growth of primary tumors, are exploited by recurrent, competent tumors and identify therapeutic targets in patients with MRD known to be at high risk of relapse. (C) 2017 AACR.